N~1羟烷基-5-氟尿嘧啶和α-5-氟尿嘧啶-N~1-二羧酸的研究

5-氟尿嘧啶(5-FU)是一种广谱性的抗肿瘤药物,其主要缺点是脂溶性小,口服吸收困难,毒副作用较大。为此,多年来,对5-FU进行了大量的化学修饰工作。已成功用于临床的5-FU衍生物主要有呋喃啶(FT-207),双呋喃啶(Thf_2-5-FU)、氟尿嘧啶脱氧核苷(FUDR)及卡莫氟(HCFU)等。在前文中,我们报道了1,3-二羟烷基-5-氟尿嘧啶和氨基酸短肽负载的5-氟尿嘧啶的合成及其抗肿瘤活性。     

含5-氟尿嘧啶的氨基酸衍生物的合成及其抗肿瘤活性研究

5-氟尿嘧啶乙酸对硝基苯酯和5-氟尿嘧啶丙酸对硝基苯酯与一系列氨基酸反应,制备了12个新的含5-氟尿嘧啶的氨基酸衍生物,并确定了化合物的结构。初步动物试验表明某些化合物有一定的抗肿瘤活性。     

主链含氨基酸、5-氟尿嘧啶、氮芥的聚磷酰胺和聚磷酸酯的合成及其抗肿瘤活性研究

由1,3-双(氨基酸丙酯盐酸盐)-5-氟尿嘧啶与双(2-氯乙基)氨基磷酰二氯在DMF中反应得到十种含氨基酸、氮芥和5-氟尿嘧啶啶三组分的聚合物。通过核磁、红外和紫外以及元素分析测定了聚合物的结构。试验了聚合物的体外抗肿瘤活性。     

主链含氨基酸、5-氟尿嘧啶和膦甲酸乙酯(膦乙酸乙酯)的聚磷酰胺和聚磷酸酯的合成及抗肿瘤活性研究

由1,3-双(氨基酸丙酯盐酸盐)-5-氟尿嘧啶与膦甲(乙)酸乙酯在DMF中反应制得二十种主链含氨基酸、膦甲(乙)酸乙酯和5-氟尿嘧啶三组分的聚合物。通过核磁、红外和紫外光谱以及元素分析测定了聚合物的结构。并试验了聚合物的体外抗肿瘤活性。     

氨基酸5-氟尿嘧啶酯类衍生物的合成及其抗肿瘤活性研究

以N-保护的氨基酸钾盐与1-(ω-溴丙基)-5-氟尿嘧啶和1-(ω-溴丁基)-5-氟尿嘧啶反应,制备了18种氨基酸的ω-(N¹-5-氟尿嘧啶基)-丙醇酯和丁醇酯的盐酸盐,并确定了它们的结构。动物试验的初步结果表明,酪氨酸、苯丙氨酸的3-(N¹-5-氟尿嘧啶基)-丙醇酯盐酸盐对小鼠艾氏腹水癌的抑制率分别为88.1%和86.7%。     

氟尿嘧啶自旋标记衍生物的合成与抗肿瘤活性

稳定氮氧自由基作为某些抗癌药物的载体,不仅能提高药物对癌细胞的选择性,而且为借助电子自旋共振(ESR)技术研究药物的作用机理和代谢提供了一种新手段。在前文中,我们报道了几种5-氟尿嘧啶的自旋标记衍生物。作为这一工作的继续,本文报道一系列新的氟尿嘧啶自旋标记衍生物10_(a—c)、11_(a—c)和12_(a—c)的合成及其抗肿瘤活性的研究。     

5-氟尿嘧啶短肽的合成及其抗肿瘤活性研究

5-氟尿嘧啶乙酸对-硝基苯酯和5-氟尿嘧啶丙酸对-硝基苯酯分别与三种二肽反应,制备了五个5-氟尿嘧啶二肽(4 a-e)。以5-氟尿嘧啶的氨基酸对-硝基苯酯(2 a-c)分别和三种二肽反应,制得四个5-氟尿嘧啶三肽(5 a-d)。产物经元素分析、NMR、IR和UV鉴定。初步动物试验表明:5-氟尿嘧啶丙酰甘-苯丙二肽,5-氟尿嘧啶乙酰甘-甘-苯丙三肽和5-氟尿嘧啶乙酰缬-亮-甘三肽对小白鼠移植性艾氏腹水癌有一定的抑制作用。     

含5-氟尿嘧啶短肽的合成及其抗肿瘤活性研究

肿瘤细胞与正常细胞在酶系上存在差别,利用这些差别,chakravarty等设计并合成缬-亮-赖三肽与苯二胺氮芥等抗肿瘤原药结合的抗肿瘤短肽药物,它们的抗肿瘤选择性比苯二胺氮芥等抗肿瘤原药提高5～7倍。我们在前文中报道了5-氟尿嘧啶乙酰(丙酰)二肽和三肽的合成及抗动物肿瘤试验,初步结果表     

N''羟烷基-5-氟尿嘧啶和α-5-氟尿嘧啶-N-二羧酸的研究

5-氟尿嘧啶是一种广谱性的抗肿瘤药物, 其缺点是脂溶性小, 毒副作用较大, 为此, 对该化合物进行了大量的化学修饰工作, 本文通过2,4,-双三甲硅基-5-氟尿嘧啶分别与乙酸-W-溴代烷基酯和α-溴代丙二酸二乙酯的反应, 然后醇解, 制备了五种N'羟烷基-5-氟尿嘧啶-(2a-e)和α-5-氟尿嘧啶-N'-丙二酸二乙酯(3), 通过5-氟尿嘧啶与衣康酸二甲酯反应, 制备了α-5-氟脲嘧啶-N'-甲基丁二酸二甲酯(4)。将以上所得到的两种α-5-氟尿嘧啶-N'-二羧酸酯水解, 制得α-5-氟尿嘧啶-N'-丙二酸(5)和α-5-氟尿嘧啶-N'-甲基丁二酸(6)。     

5-氟尿嘧啶短钛的合成及其抗肿瘤活性研究

5-氟尿嘧啶乙酸对-硝基苯酯和5-氟尿嘧啶丙酸对-硝基苯酯分别与三种二肽反应,制备了五个5-氟尿嘧啶二肽(4aα-e).以5-氟尿嘧啶的氨基酸对-硝基苯酯(2a-c)分别和三种二肽反应,制得四个5-氟尿嘧啶三肽(5A-d).产物经元素分析,NMR,IR和UV鉴定.初步动物试验表明:5-氟尿嘧啶丙酰甘-苯丙二肽,5-氟尿嘧啶乙酰甘-甘-苯丙三肽和5-氟尿嘧啶乙酰缬-亮-甘三肽对小白鼠移植性艾氏腹水癌有一定的抑制作用.     

Convenient and Efficient Synthesis of 11‐Amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone Derivatives

The Gewald reactions of 5‐substituted‐1,3‐cyclohexanedione, malononitrile, and powdered sulfur were carried out to give the corresponding products 2‐amino‐5‐substituted‐7‐oxo‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile derivatives 1 . The intermediate enamines 2 were prepared by reaction of compounds 1 and 5‐substituted‐1,3‐cyclohexanedione with hydrochloric acid as catalyst. The title compounds 11‐amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone 3 were synthesized by cyclization of compounds 2 in the presence of K₂CO₃ and Cu₂Cl₂. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H‐NMR spectra.     

Diastereoselective synthesis of highly functionalized β2,2,3-substituted amino acids from 4-substituted-1,3-oxazinan-6-ones

1,3-Oxazinan-6-ones were used to generate substituted β^2,2,3-substituted amino acid derivatives. The enolates of 1,3-oxazinan-6-ones were trans-selectively intercepted with electrophiles. This alkylation was subsequently optimized for a one-pot dialkylation to form 5,5-disubstituted oxazinanones. The initial 5-monomethylated compounds could be enolized and then diastereoselectively intercepted with different electrophiles to form differentially 5,5-disubstituted products. The 5,5-dialkylated oxazinanones were then transformed to N-methyl β^2,2,3-substituted amino acids by reductive cleavage. Hydrolysis or solvolysis of the oxazinanones afforded β^2,2,3-substituted amino acids or esters, respectively. The chemistry thus provides access to a range of symmetrical and stereopure β^2,2,3-substituted amino acids and further establishes 1,3-oxazinan-6-ones as useful intermediates.     

Synthesis of polyurethanes containing nucleic acid base derivatives as grafted pendants and their precursor amino functionalized polyurethane

A new route to polyurethanes containing nucleic acid base derivatives as grafted pendants have been established. The method is based on the grafting of 2-(thymin-1-yl)propionic acid (TPA) or 2-(adenin-9-yl)propionic acid (APA) onto amino functionalized polyurethane, poly[2-amino-2-methyl-1,3-propylene methylene bis(4-phenyl carbamate)] (PU-NH₂, IX ) at the primary amino group by the N-hydroxy compound of active ester technique. Two novel polymer models of polynucleic acid—poly[2-(2′-(thymin-1′-yl) propionamido)-2-methyl-1,3-propylene methylene bis(4-phenylcarbamate)] (PU–NHT, X ) and poly[2-(2′-(adenin-9′-yl)propionamido)-2-methyl-1,3-propylene methylene bis(4-phenylcarbamate)] (PU–NHA-40, XI )—were obtained. The amino functional polyurethane was prepared by the following three step reactions; (1) Selective N-protection of N-benzyloxycarbonyloxy-5-norbornene-2,3-dicarbonimide (CbzONB) with 2-amino-2-methyl-1,3-propanediol gave the N-protecting diol monomer 2-benzyloxycarbonylamino-2-methyl-1,3-propanediol (CbzAMP); (2) N-Protecting polurethane poly(2-benzyloxycarbonylamino-2-methyl-methyl-1,3) propylene methylene bis(4-phenylcarbamate) (PU–NHCbz, VIII ) was obtained by the polyaddition of 4,4′-diphenyl-methane diisocyanate (MDI) with CbzAMP. (3) Deprotection of PU–NHCbz produced amino polyurethane PU-NH₂. Prior to polymer synthesis, the amidation of APA with 3-aminoheptane or diethylamine were carried out as a model reaction study and the related monomer model compounds were prepared by the same methods.     

Synthesis of Spiro‐Heterocycles with the Thiazolidinone Moiety from Nitrilimines

The 2‐phenylimino‐1,3‐thiazolidin‐4‐one 2 was obtained by thermal cyclization of 4‐amino‐5‐phen‐yl‐3, 5‐thiaaza‐4‐pentenoic acid 1 using DCC as dehydration agent. Treatment of 2‐phenylimino‐1,3‐thiazolidin‐4‐one 2 with various hydrazonoyl halides 3 (nitrilimines 4 precursor) yielded 6‐aryl‐9‐phenyl‐8‐substituted‐1,4,6,7,9‐thiatetrazaspiro‐[4.4]non‐7‐en‐3‐ones 5a‐1. Both analytical and spectroscopic data of all the synthesized compounds are in full agreement with the proposed structures.     

Selenium-sulfur analogs. 4. Synthesis and characterization of (±)-β-(2-amino-1,3-selenazol-4-yl)alanine

The novel amino acid (±)-β-(2-amino-1,3-selenazol-4-yl)alanine 4a was prepared from selenourea and 1,3-dichloropropan-2-one via a four-step synthetic sequence. Nuclear magnetic resonance analysis indicated a downfield chemical shift of δ 0.29 to 0.30 and δ 0.57 for the C₅-proton of the protonated 2-amino-and 2-acetamido-1,3-selenazoles respectively compared with the analogous thiazoles. The infrared spectra of the selenazole and corresponding thiazole compounds were virtually identical.     

A new synthesis of α-amino acids—III: Amidoalkylation of active methylene compounds with glyoxylic acid derivatives

The synthesis of N-acyl derivatives of γ - keto - α - amino acids (3, 4, 5) by the amidoalkylation of 1,3-dicarbonyl compounds with glyoxylic acid-amide adducts (1, 2) is described. The γ - keto - α - amino acid derivatives (4, 5) were further converted to the corresponding butenolides (6, 7) and to pyrazolylglycine (12).     

The Convenient Synthesis of 11‐Methyl‐3,8‐disubstituted‐12‐aryl‐3,4,7,8,9,12‐hexahydro‐1H‐chromeno[2,3‐b]quinoline‐1,10(2H)‐dione Derivatives

The 2‐arylidene‐3‐oxobutanenitrile derivatives 2 were prepared by the Knoevenagel condensation between aldehydes and 3‐oxobutanenitrile 1 , which was obtained by acid hydrolysis of β‐aminocrotononitrile. 3‐Acetyl‐2‐amino‐4H‐chromen‐5(6H)‐one derivatives 3 were synthesized by reaction of 2‐arylidene‐3‐oxobutanenitrile 2 and 5‐substituted‐1,3‐cyclohexanedione in ethylene glycol. The 11‐methyl‐3,8‐disubstituted‐12‐aryl‐3,4,7,8,9,12‐hexahydro‐1H‐chromeno[2,3‐b]quinoline‐1,10(2H)‐dione derivatives 4 were obtained by Friedländer reaction of compounds 3 with 5‐substituted‐1,3‐cyclohexanedione, using p‐toluenesulfonic acid monohydrate as catalyst. The structures of all novel compounds were characterized by elemental analysis, IR, MS, and ¹H NMR spectra. The crystal and molecular structure of compound 4f has been determined by single crystal XRD analysis.     

Synthesis of Thieno[2,3‐b]quinolinone Derivatives

The Knoevenagel reactions of malononitrile with acetophenone or 4‐substituted acetophenons were carried to give the corresponding 2‐(1‐aryle thylidene)malononitriles, which was further cyclized with sulfur using NaHCO₃ as catalysts to generate 2‐amino‐5‐arylthiophene‐3‐carbonitrile 2 . The intermediate enamines 3 were prepared by refluxing of 2 with 5‐substituted‐1,3‐cyclohexanedione using p‐toluenesulfonic acid as catalyst. The title compounds 4‐amino‐3‐aryl ‐7‐substituted‐7,8‐dihydrothieno[2,3‐b]quinolin‐5(6H)‐one were synthesized by cyclization of 3 in the presence of K₂CO₃ and Cu₂Cl₂. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H‐NMR spectra.     

Antimicrobial Activity of Some Novel Thiourea,Hydrazine, Fused Pyrimidine and 2‐(4‐Substituted)anilinobenzoazole Derivatives Containing Sulfonamido Moieties

Thiophosgenation of sulfonamides 1a‐c in the presence of dilute HCl at room temperature furnished the isothiocyanatosulfonamides 2a‐c and treatment with aromatic amines gave 1,3‐disubstituted thioureas 3a,b . Also, interaction of two molecules of 2c with 1,4‐phenylenediamine yielded the novel bisthiourea 4 . Cyclocondensation of 2 with ortho amino carboxylic acid compounds such as anthranilic acids 8 , 5‐amino‐1‐phenyl‐pyrazol‐4‐carboxylic acid 9 and 4,5,6,7‐tetrahydro‐2‐amino‐benzo[b]thiophene‐3‐carboxylic acid 10 furnished the fused thiopyrimidines 11a‐d, 12 and 13 , respectively. 2‐Anilinobenzoazole derivatives 15a‐c, 16a, b and 17a,b were obtained through cyclocondensation of 2 with 1,2‐dinucleophiles.     

A Convenient Synthesis of 3-Benzoylindolizine-5-carbaldehydes

3-Benzoylindolizine-5-carbaldehydes (4a-f), which could be used as derivatization reagents for amino compounds in HPCE were synthesized based on the 1,3-dipolar cycloaddition of 1-phenacyl-2-(1,3-dioxolan-2-yl)pyridinium ylide with alkenes in the presence of TPCD.